A primeira dosagem sérica de tireoglobulina estimulada pós-operatória é um fator prognóstico para os microcarcinomas da tireoide

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Brazilian

Journal

of

OTORHINOLARYNGOLOGY

ORIGINAL

ARTICLE

The

first

postoperative-stimulated

serum

thyroglobulin

is

a

prognostic

factor

for

thyroid

microcarcinomas

夽

Isabela

de

Oliveira

Amui

_,

_José

_Vicente

_Tagliarini

_,

_Emanuel

_C.

_Castilho

_,

Mariângela

de

Alencar

Marques

_,

_Yoshio

_Kiy

_,

_José

_Eduardo

_Corrente

_,

Gláucia

M.F.S.

Mazeto

a_{UniversidadeEstadualPaulista‘‘JúliodeMesquitaFilho’’(Unesp),FaculdadedeMedicinadeBotucatu,Departamentode}

MedicinaInterna,Botucatu,SP,Brazil

b_{UniversidadeEstadualPaulista‘‘JúliodeMesquitaFilho’’(Unesp),FaculdadedeMedicinadeBotucatu,Departamentode}

Oftalmologia,OtorrinolaringologiaeCirurgiadeCabec¸aePescoc¸o,Botucatu,SP,Brazil

c_{UniversidadeEstadualPaulista‘‘JúliodeMesquitaFilho’’(Unesp),FaculdadedeMedicinadeBotucatu,Departamentode}

Patologia,Botucatu,SP,Brazil

d_{UniversidadeEstadualPaulista‘‘JúliodeMesquitaFilho’’(Unesp),FaculdadedeMedicinadeBotucatu,Departamentode}

Doenc¸asTropicaiseDiagnósticoporImagem,Botucatu,SP,Brazil

e_{UniversidadeEstadualPaulista‘‘JúliodeMesquitaFilho’’(Unesp),InstitutodeBiociências,DepartamentodeBioestatística,}

Botucatu,SP,Brazil

Received27July2017;accepted7October2017 Availableonline31October2017

KEYWORDS Biologicalmarkers; Clinicalevolution; Prognosis; Thyroglobulin; Thyroidneoplasms Abstract

Introduction:Endogenous thyroid-stimulating hormone-stimulated thyroglobulin collected aftertotalthyroidectomyisausefulpredictorofbetterprognosisinpatientswithdifferentiated thyroidcarcinomasingeneral,butstudieswithmicrocarcinomasarescarce.

Objective: Toassesswhetherthefirstpostoperativestimulatedthyroglobulinmeasurementis aprognosticfactorinpatientswithmicrocarcinoma.

Methods:Themedicaldataof150differentiatedthyroidcarcinomapatientswerestudied ret-rospectively,and54(36%)caseswithmicrocarcinomawereselected.Thefirstpostoperative stimulatedthyroglobulin(1ststimulatedthyroglobulin),measuredafterthyroidectomy,initial presentationdata,andmicrocarcinomastreatmentwereassessedregardingoutcome.Worse prognosiswasdefinedasneoplasmpersistence/recurrence.

Results:Persistence/recurrence occurred in 27.8% ofthe cases. These patients were iden-tified according to the following parameters: receiving more than one 131_{iodine dose}

(100% vs. 0%; p<0.0001); accumulated 131_{iodine dose (232.14±99.09 vs. 144±33.61mCi;}

夽 _{Pleasecitethisarticleas:AmuiIO,TagliariniJV,CastilhoEC,MarquesMA,KiyY,CorrenteJE,etal.Thefirstpostoperative-stimulated}

serumthyroglobulinisaprognosticfactorforthyroidmicrocarcinomas.BrazJOtorhinolaryngol.2019;85:37---42.

∗_{Correspondingauthor.}

E-mail:gmazeto@fmb.unesp.br(G.M.Mazeto).

PeerReviewundertheresponsibilityofAssociac¸ãoBrasileiradeOtorrinolaringologiaeCirurgiaCérvico-Facial.

https://doi.org/10.1016/j.bjorl.2017.10.005

1808-8694/©2017Associac¸˜aoBrasileiradeOtorrinolaringologiaeCirurgiaC´ervico-Facial.PublishedbyElsevierEditoraLtda.Thisisanopen accessarticleundertheCCBYlicense(http://creativecommons.org/licenses/by/4.0/).

p<0.0001);presentedactivediseaseinthelastassessment(53.3%vs.0%;p<0.0001); follow-uptime(103.07_±61.27vs.66.85_±70.14months;p=0.019);and1ststimulatedthyroglobulin (19.01±44.18 vs. 2.19±2.54ng/dL; p<0.0001). After multivariate logisticregression, only the 1stSTg[oddsratio=1.242; 95% confidenceinterval:1.022---1.509; p=0.029] and follow-uptime(oddsratio=1.027;95%confidenceinterval:1.007---1.048;p=0.007)wereindependent predictorsofriskofpersistence/recurrence.Thecutoffpointof1.6ng/dLforthe1ststimulated thyroglobulinwassignificantlyassociatedwithdiseasepersistence/recurrence[areaunderthe curve=0.713(p=0.019)].

Conclusion:The first stimulated thyroglobulin predicted disease persistence/recurrence in patientswithmicrocarcinoma.

© 2017 Associac¸˜ao Brasileira de Otorrinolaringologia e Cirurgia C´ervico-Facial. Published by Elsevier Editora Ltda. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).

PALAVRAS-CHAVE

Marcadores biológicos; Evoluc¸ãoclínica; Prognóstico; Tireoglobulina; Neoplasiasda tireoide

Aprimeiradosagemséricadetireoglobulinaestimuladapós-operatóriaéumfator prognósticoparaosmicrocarcinomasdatireoide

Resumo

Introduc¸ão: A tireoglobulina estimulada pelohormônio tireoestimulanteendógeno coletada apóstireoidectomiatotaléumpreditorútildemelhorprognósticoempacientescom carcino-masdiferenciadosdetireoideemgeral,masosestudoscommicrocarcinomassãoescassos. Objetivo:Avaliarseaprimeiramedidapós-operatóriadetireoglobulinaestimuladaéumfator prognósticoempacientescommicrocarcinoma.

Método: Osdadosclínicosde150pacientescomcarcinomadiferenciadodetireoideforam estu-dadosretrospectivamentee54(36%)casoscommicrocarcinomaforamselecionados.Aprimeira dosagemdetireoglobulinaestimulada(1a_{TgE)pós-operatória,medidaapósatireoidectomia,}

osdadosdaapresentac¸ãoinicialetratamentodomicrocarcinomaforamavaliadosquantoao resultado.Opiorprognósticofoidefinidocomoapersistência/recorrênciadaneoplasia. Resultados: Apersistência/recorrênciaocorreuem27,8%doscasos.Essespacientesforam iden-tificados de acordocomos seguintes parâmetros: receberam mais de umadose de iodo131

(100% vs. 0%; p<0,0001); dose acumulada de iodo131 _{(232,14±99,09 vs. 144±33,61 mCi;}

p<0,0001); apresentou doenc¸a ativa naúltimaavaliac¸ão(53,3% vs. 0%; p<0,0001); tempo deseguimento(103,07±61,27vs.66,85±70,14meses;p=0,019);e1aTgE(19,01±44,18vs. 2,19±2,54ng/dL;p<0,0001). Apósaregressãologísticamultivariada, apenasa1aTgE[odds ratio=1.242;intervalodeconfianc¸ade95%:1,022-1,509;p=0,029]etempo deseguimento (oddsratio=1,027; intervalode confianc¸ade 95%:1,007-1,048; p=0,007)foram preditores independentesderiscodepersistência/recorrência.Opontodecortede1,6ng/dLparaa1aTgE foisignificativamenteassociadoàpersistência/recidivadadoenc¸a[áreaabaixodacurva=0,713 (p=0,019)].

Conclusão:A1adosagemséricadetireoglobulinaestimuladapreviuapersistência/recorrência dadoenc¸aempacientescommicrocarcinoma.

© 2017 Associac¸˜ao Brasileira de Otorrinolaringologia e Cirurgia C´ervico-Facial. Publicado por Elsevier Editora Ltda. Este ´e um artigo Open Access sob uma licenc¸a CC BY (http:// creativecommons.org/licenses/by/4.0/).

Introduction

The incidence of differentiated thyroid carcinoma (DTCs) has been growing significantly,1 _{especially because of}

higher microcarcinoma (TMC) frequency.2,3 _{Although TMC}

are generally associated with excellent prognosis,4 _some

patientshave moreaggressive tumors,resulting inhigher rates of persistency/recurrence and activedisease in the long-term follow-up.5 _{Thus, many TMC-related clinical,}

histopathological, and molecular parameterswith varying complexities and costs have been assessed in the search

for markers that can predict higher aggressiveness and worse prognosis.6 _{Nevertheless, these parameters vary}

fromonestudytoanother,andthefactorsassociatedwith worseprognosishavenotyetbeencompletelyestablished, preventingconsensusonthemosteffectiveTMCtreatment approach. Largertumors,multifocality,andcapsular inva-sion have been associated with lymph node metastasis,7

while younger age, multifocality, subcapsular location, extrathyroidal extension, intraglandular tumor fibrosis, and BRAF mutation have been associated with higher recurrence.8,9

In thiscontext, asingleserumthyroid-stimulating hor-mone (TSH)-stimulated thyroglobulin (STg) measurement aftertotalthyroidectomy hasbeen useful forpredicting a betterprognosis inDTC patients.10 _{Yetstudies thatassess}

thisparameterspecificallyinpatientswithTMCarescarce. ThisstudyassessedwhetherthefirstpostoperativeSTg mea-surementisaprognosticfactorinTMCpatients.

Methods

This retrospective study assessed the clinical course of TMC patients and compared the first postoperative STg (1stSTg), and many other clinical, laboratory, and ther-apeutic parameters of patients with and without tumor persistence/recurrenceafter initial treatment. This study wasapprovedbytheResearchEthicsCommitteeofthe insti-tutioninwhichitwasconducted(protocoln◦4288-2012).

Patients

The medicaldata of 150 latepostoperative DTC patients wereassessed.Thepatientswerebeingfollowedinan out-patient clinic of thyroid neoplasms of a tertiary hospital inBrazil. Fifty-four(36%) TMCpatients submittedtototal thyroidectomy(TT)between1994and2010wereselected. Thesepatientsdidnothaveotherthyroidneoplasms,were not positive for antithyroglobulin antibodies (TgAb), had postoperative follow-up of at least 24 months, and were takinglevothyroxine.

The service’s treatment/follow-up protocol of DTC patients atthe timethecases wereenrolledin thestudy consisted of TT, followed by diagnostic whole-body scan (WBS),andserumendogenousTSH-stimulatedthyroglobulin (1stSTg)measurementthreemonthsafterTT.Thepatients then receivedanablative/therapeutic doseof radioactive iodine (TDI) followed by confirmatory WBS 5 days later. One year after TDI, STg and TSH were measured, and a neck ultrasound (US) was performed. Clinical and labo-ratory assessments were performed each 4 or 6 months, whichincludeddosingofserumTSH,freethyroxine(FT4), TgAb, and thyroglobulin (Tg). Neck US and chest X-ray were performed annually, and other imaging tests [chest computedtomography(CT),abdominalUS,neckand medi-astinal magnetic resonance imaging (MRI), new WBS and positronemissiontomography(PET-CT)]orcytohistological testswererequesteduponsuspicionofactivedisease.

TMCsweredefinedastumorsobservedinthe histopatho-logical analysiswithlargestdiameterof1.0cmorsmaller andhistologicaldiagnosisofpapillarycarcinoma(PC), fol-licularcarcinoma(FC),orHürthlecellcarcinoma.11

Studyparameters

The main variable of interest was the 1stSTg. Neverthe-less, the general characteristics of the patients, initial presentation of the neoplasm, treatment, and disease outcome were alsoassessed. Cases with and without dis-ease persistence/recurrencewere compared withregards to these parameters to determine possible predictors of theoutcomepersistence/recurrence.Patientswereinitially

characterizedby gender, ageat the timeof surgery, self-reported race, and initial disease presentation, which considered thefollowing: tumor characteristics andstage [risk of recurrence (LATS) and mortality (TNM)],12,13 _first

postoperative WBS (WBS was considered positive if any uptakeinanysegmentwasdetected byscintigraphy),and percentage of 131_{Iodine (}131_{I) uptake. Treatment-related} aspectswerealsoassessed,suchasneckdissectionduring TT, number of 131_{I doses,and total accumulated dose (in} mCi).

Diseaseoutcomewasassessedmainlyaccordingtotumor persistenceor recurrence.The followingwere also evalu-ated: patient’s condition in the last assessment, whether withor without active disease;disease-free survival time (inmonths);andfollow-uptime(inmonths).Disease persis-tenceorrecurrencewasdefinedasSTg≥2ng/mL,oractive diseaseevidencedbyimagingtestsorbiopsyoneyearafter theinitialtreatment(TTandWBS).14,15_{Activetumorinthe}

lastassessmentwasdefinedasdeathcausedbythetumoror presenceofthesamecriteriausedfordefiningpersistence orrecurrence.

FT4, TSH, and Tg were determined by chemi-luminescence(DPC, Los Angeles, CA, USA) at the clinical laboratoryofHospitaldasClínicas---FaculdadedeMedicina deBotucatu. The referencevalues for FT4 andTSH were 0.80---1.90ng/dL and 0.40---4.0␮IU/mL, respectively, while thoseforTgwere0.83---68.0ng/mL.Tganalyticaland func-tionalsensitivitieswere0.2ng/mLand0.9ng/mL(forvalues higherthan2ng/mL),respectively.

Statisticalanalyses

The variablesunderwentunivariate analysisin relation to tumorpersistenceor recurrence.Only agehadsymmetric distribution,soitwasassessedbytheStudent’st-test.The othernumericalvariables(means±standarddeviations,SD) wereadjustedbythegeneralizedlinearmodelwithagamma distribution (asymmetric). The qualitative variables (per-centages)were assessedby theFisher’sexact test.Later, multivariate logistic regression was performed with the univariate analysis variables with p≤0.15. The response variablewastumorpersistenceorrecurrence.Thevariables wereselectedbythestepwisemethod.

A receiver-operating characteristics (ROC) curve was constructedforthe1stSTgtoestablishthecutoffand deter-minethemarker’ssensitivityandspecificitytopredicttumor persistenceorrecurrence.Thesignificancelevelwassetat 5%(p<0.05).

Results

Table 1 shows the patients’ general data. Five patients (9.3%) had recurrence and 15 (27.8%) had persis-tence/recurrence,ofwhich8(53.3%)stillpresentedactive diseaseinthelastmedicalassessment.Distantmetastases ordeathsduringthefollow-upperioddidnotoccur.

The group with disease persistence/recurrence had higher 1stSTg level (p<0.0001), accumulated 131_iodine dose(p<0.0001),follow-uptime(p=0.019),percentageof patientswhoreceivedtwoor more131_{Idoses(p<0.0001),}

Table1 Clinicalandhistopathologicaldataofpatients. Generaldata

Female,n(%)a _48(88.9)

Whitereportedcolor,n(%)a _53(98.2)

Age(years)b _46.30±13.58

Follow-up(months)b _76.91±69.19

Totalthyroidectomy,n(%)a

Onestage 33(61.1)

Twostages 21(38.9)

Lymphnodedissection,n(%)a _16(29.6)

Histologicalsubtypes,n(%)a Papillarycarcinoma Classic 41(75.9) Follicularvariant 8(14.8) Sclerosing 1(1.8) Mucinous 1(1.8) Columnarcells 1(1.8) Oncocyticcells 1(1.8) Follicular 1(1.8) Tumorsize(cm)b _0.61±0.30 Multifocality,n(%)a _20(37.0) Bilaterality,n(%)b _15(27.8) Tumorcapsule,n(%)a Complete 13(24.1) Incomplete 8(14.8) Absent 33(61.1)

Lymphnodemetastases,n (%)a 7(13) TNMstaging,n(%)a I 44(81.5) III 1(1.8) IV 9(16.7)

1stwholebodyscanpositive, n(%)a

51(94.4) 1stThyroglobulinstimulated

(ng/dL)b

6.72±23.6 Numberofdosesof131Iodine,n(%)a

0 1(1.9)

1 44(81.5)

2 8(14.8)

3 1(1.9)

Iodineuptake(%)b _1.51±1.65

Cumulativedoseof131Iodine (mCi)b

167.79_±69.84

Recurrence,n(%)a _5(9.3)

Persistence/recurrence,n(%)a _15(27.8)

Activediseaseinthelast medicalevaluation,n(%)a

8(14.8) Disease-freesurvival

(months)b

42.06±65.03

cm,centimeters;mCi,milicuries;n,number;ng/dL,nanograms per decilitre; %, percentage; TNM, tumor-node-metastases, stagingsystem of the American Joint Commissionon Cancer (AJCC).13

a_{Frequenciesandpercentagesforcategoricalvariables.} b _{Mean±standarddeviation.}

andpercentageof patientswithactivediseasein thelast assessment(p<0.0001)(Table2).

In multivariate logistic regression, 1stSTg [odds ratio (OR)=1.242; 95% confidence interval (CI): 1.022---1.509;

p=0.029] and follow-up time (OR=1.027; 95% CI: 1.007---1.048; p=0.007) were independent predictors ofriskofDTCpersistence/recurrence.

BasedontheROCcurve,the1stSTgcutoffof1.6ng/dL was associated witha sensitivity of 70% and a specificity of 60% (areaunderthe curve=0.713; p=0.019) for tumor persistence/recurrence(Fig.1).Mostpatients(71.4%)with 1stSTglevelequal toor greaterthan 1.6ng/dLhad tumor persistence/recurrence, and most cases (60.5%) with STg levelbelow1.6ng/dLdidnot(Fig.2).

Discussion

Serum STg determination after TT and before 131_I abla-tion,hereincalled1stSTg,couldhelptopredicttheinitial response to therapy and DTC prognosis.10,16,17 _However,

most studiesassess DTCin generalanddonot investigate the 1stSTg specifically in patients with TMC. This study foundthat1stSTgcanbeanindependentpredictorof car-cinomapersistence/recurrencealsoforthesetumors.This marker remainedsignificant even whenassessed together with other parameters frequently associated with TMC prognosis.8,9,18---20

An important topicof discussion is the optimal 1stSTg cutoff for the prognosis. For DTCs in general, levels between20and30ng/mLhavebeenassociatedwithhigher sensitivity and specificity for predicting disease persis-tence/recurrence,whilelevels<1---2ng/mLwouldbestrong predictors of remission.4 _{In a recent meta-analysis with}

almost 4000 patients, Webb et al. found high negative predictive valuefor disease-freestatuswhen pre-ablation serum Tg was below 10ng/mL.10 _{However, the exact Tg}

levels required to prognosticate DTCs in general or TMCs havenotbeenestablishedastheydependonmanyfactors, suchasTSHlevel,16 _{assaysensitivity,andamount of}

resid-ualtissue,amongothers.4_{Thecutofffoundbythepresent}

studyforTMC(1.6ng/dL)wasmuchlowerthanthecutoffs mentioned earlier,with70%sensitivityand60% specificity topredictdiseasepersistence/recurrence.Thisfindingmay be explained by many reasons. First, considering that all thestudypatientsunderwentTT,andthe131_Iuptakeafter surgery and before ablation was relatively low, we infer that theremainingcervical tissuemust havebeen scanty, whichcouldatleastpartlyexplainthelowercutoffs. More-over,sinceTgtendstoreachitsnadiraroundthreetofour weeksafterTT,4_{itcouldhavecontinuedtodecreaseafter}

this initial period.15 _{Hence, since we assessed STg about}

threemonthsaftersurgery,thislongerintervalcouldhave contributedtothelowercutoffs.

Althoughtherateof TMCrecurrenceis nothigh, espe-ciallyinpatientssubmittedtoTT,21_{itisnotnegligible.The}

study rates of disease persistence/recurrence and active disease in the last assessment were almost 30% and 15%, respectively. Therefore, we believe that the therapeutic approachshouldbeindividualized,andthatSTgcouldbeone oftheparametersincluded inthisindividualization.Based onthisstudyresults,inpatientswithnegativeTgAb,aSTg

Table 2 Comparative analysisa _{of clinical and histopathological data between patients with and without cancer}

persistence/recurrence.

Generaldata Persistence/recurrenceofthedisease p

Non=39(72.2%) Yes n=15(27.8%)

Age(years) 44.87_±13.19 50.00_±14.32 0.217

Female,n(%) 36(92.3) 12(80.0) 0.197

Totalthyroidectomyintwostages,n(%) 15(38.5) 6(40.0) 0.917

Lymphnodedissection,n(%) 10(25.6) 6(40.0) 0.301

Tumorsize(cm) 0.63_±0.29 0.57_±0.33 0.618

Multifocality,n(%) 15(38.5) 5(33.3) 0.727

Bilaterality,n(%) 11(28.2) 4(26.7) 0.946

Classicpapillarycarcinoma,n(%) 31(79.5) 10(66.7) 0.324

Encapsulatedtumor,n(%) 8(20.5) 5(33.3) 0.324

Invasionoftumorcapsule,n(%) 4(10.3) 3(20.0) 0.306

Lymphnodemetastases,n(%) 5(12.8) 2(13.3) 0.960

Contralaterallymphnodemetastases,n(%) 2(5.1) 2(13.3) 0.147

TNMIII/IV,n(%) 8(20.5) 2(13.3) 0.543

1stthyroglobulinstimulated(ng/dL) 2.19±2.54 19.01±44.18 <0.0001

131_{Iodineuptake(%) 1.57±1.65 1.36±1.45 0.687}

1stwholebodyscanpositive,n(%) 36(92.3) 15(100.0) 0.269

Cumulativedoseof131_{Iodine(mCi) 144.08±33.61 232.14±99.09 <0.0001}

Follow-up(months) 66.85±70.14 103.07±61.27 0.019

Twoormoredosesof131_{Iodine,n(%) 0(0.0) 9(60.0) <0.0001}

Disease-freesurvival(months) 39.44±69.56 48.87±52.97 0.116

Activediseaseinthelastevaluation,n(%) 0(0.0) 8(53.3) <0.0001

cm,centimeters;mCi,milicuries;n,number;ng/dL,nanogramsperdecilitre;%,percentage.

a _{Univariateanalysisofcategoricalvariables(nand%;Fisher’sexacttest)andnumerical[mean±standarddeviation;Student’sttest}

forageandadjustmentforgeneralizedlinearmodelwithgammadistribution(asymmetrically),fortheothervariables]forthepresence ofpersistenceand/orrecurrenceofcancer.Significance:p<0.05.Thevariableswithp_≤0.15intheunivariateanalysiswereevaluated subsequentlybythemultivariateanalysis.

ROC Curve 1.0 1.0 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.2 0.0 0.0 1 - Specificity Sensitivity

Figure1 Receiver-operatingcharacteristiccurve(ROC)ofthe first stimulated thyroglobulin [cutoff=1.6ng/dL (area under the curve: 0.713; p=0.019)] as predictor of cancer persis-tence/recurrence.

levelbelow2ng/dL,measuredinthefirstthreemonthsafter TTandbeforeeventualtherapeutic131_{Idose,indicatesgood} prognosisinTMCpatients.

The limitations of thisstudy couldhaveinfluenced the resultsandinclude:itsretrospectivecharacter,themodest samplesize,thevarioushistologicsubtypesincluded(some ofthemwithworseprognosis),theinabilitytoclassifythe cases according toinitial disease presentation (incidental

80 70 60 50 40 30 20 10 0 < 1.60 > 1.60 1st stimulated thyroglobulin (ng/dL) P ersistence/Recurrence (%) p=0.041

Figure 2 Persistence/recurrence of the tumor in relation tothefirst stimulatedthyroglobulin (smaller orgreater than 1.60ng/dL).Chi-squaretest.Significance:p<0.05.

ornon-incidentalTMC),22,23_{andtheinitialtreatmentofthe}

patients(totalthyroidectomyandtherapeuticdoseof131_I), whichhasnotbeencurrentlyindicatedforTMC.4

Neverthe-less,thisstudy’s meritis bringingtolight the importance of measuring STg after thyroidectomy to prognosticate TMC.

Conclusion

The first postoperative STg measurement was capable of predictingTMCpersistence/recurrence.Otherstudieswith largersample sizes anddifferentdesignsarenecessary to confirmtheseresults.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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